Publications by authors named "Beverly A Teicher"

112 Publications

Format (2D vs 3D) and media effect target expression and response of patient-derived and standard NSCLC lines to EGFR inhibitors.

Cancer Treat Res Commun 2021 Sep 25;29:100463. Epub 2021 Sep 25.

DCTD National Cancer Institute, Bethesda, MD, United States. Electronic address:

Three patient-derived NSCLC lines and three well-established NSCLC lines with varied EGFR gene status were compared for expression of EGFR protein, proliferation and epithelial and mesenchymal markers in monolayer, simple spheroid and complex spheroid cultures. The effects of diverse culture conditions and exposure time on the response of the six NSCLC lines to the EGFR inhibitors erlotinib, afatinib, lapatinib, and osimertinib were examined. The clinical Cmax was used as the test concentration to determine whether cells were responsive or resistant to each agent. Among the patient-derived lines, LG0703-F948, which has an EGFR L858R mutation, was responsive to each of the four EGFR inhibitor when grown as spheroids but resistant when grown in monolayer. The HCC827 line, which carries an EGFR E746-A750 deletion, was responsive to each of the four EGFR inhibitors when grown as spheroids or monolayers. NCI-H1975 cells which have an EGFR T790M mutation and an EGFR L858R mutation, were sensitive to osimertinib when propagated as spheroids but not when grown in monolayer. The results suggest that the expression of cell surface targets and response to drugs targeting cell surface proteins varies depending upon cell culture format. These findings may help to explain, in part, the concordance or discordance between cell culture and in vivo findings in experimental systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctarc.2021.100463DOI Listing
September 2021

In vivo evaluation of the lysine-specific demethylase (KDM1A/LSD1) inhibitor SP-2577 (Seclidemstat) against pediatric sarcoma preclinical models: A report from the Pediatric Preclinical Testing Consortium (PPTC).

Pediatr Blood Cancer 2021 Nov 28;68(11):e29304. Epub 2021 Aug 28.

Greehey Children's Cancer Research Institute, San Antonio, Texas, USA.

SP-2577(Seclidemstat), an inhibitor of lysine-specific demthylase KDM1A (LSD1) that is overexpressed in pediatric sarcomas, was evaluated against pediatric sarcoma xenografts. SP-2577 (100 mg/kg/day × 28 days) statistically significantly (p < .05) inhibited growth of three of eight Ewing sarcoma (EwS), four of five rhabdomyosarcoma (RMS), and four of six osteosarcoma (OS) xenografts. The increase in EFS T/C was modest (<1.5) for all models except RMS Rh10 (EFS T/C = 2.8). There were no tumor regressions or consistent changes in dimethyl histone H3(K4), HOXM1, DAX1, c-MYC and N-MYC, or tumor histology/differentiation. SP-2577 has limited activity against these pediatric sarcoma models at the dose and schedule evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29304DOI Listing
November 2021

SMAC Mimetic/IAP Inhibitor Birinapant Enhances Radiosensitivity of Glioblastoma Multiforme.

Radiat Res 2021 06;195(6):549-560

Molecular Radiation Therapeutics Branch, National Cancer Institute, Rockville, Maryland 20850.

Birinapant is a novel SMAC peptidomimetic molecule in clinical development. It suppresses the inhibitor of apoptosis proteins (IAPs) and promotes cytochrome-C/Apaf-1/caspase-9 activation to induce effective apoptosis. Because IAP inhibition has been shown to enhance the sensitivity of cancer cells to radiation, we investigated the role of birinapant in radiosensitization of glioblastoma cells in vitro and in vivo. Two glioblastoma cell lines, U-251 and U-87, were used to analyze radiosensitization in vitro with 7-AAD cell death/apoptosis and clonogenic assays. Subcutaneous flank (U-251 and U-87) and intracranial orthotopic (U-251) xenografts in nude mice were used to evaluate radiosensitization in vivo. TNF-α levels in media and serum were measured using electrochemiluminescence. Radiosensitization in vitro was more prominent for U-251 cells than for U-87 cells. In vivo, in both tumor models, significant tumor growth delay was observed with combination treatment compared to radiation alone. There was a survival benefit with combination treatment in the orthotopic U-251 model. TNF-α levels in media correlated directly with radiation dose in vitro. These findings show that birinapant can enhance the radiosensitivity of glioblastoma cell lines in cell-based assays and tumor models via radiation-induced TNF-α. Further study into the use of birinapant with radiation therapy is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1667/RADE-20-00171.1DOI Listing
June 2021

F-aza-T-dCyd (NSC801845), a Novel Cytidine Analog, in Comparative Cell Culture and Xenograft Studies with the Clinical Candidates T-dCyd, F-T-dCyd, and Aza-T-dCyd.

Mol Cancer Ther 2021 04;20(4):625-631

Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland.

In this article, 5-aza-4'-thio-2'-β-fluoro-2'-deoxycytidine (F-aza-T-dCyd, NSC801845), a novel cytidine analog, is first disclosed and compared with T-dCyd, F-T-dCyd, and aza-T-dCyd in cell culture and mouse xenograft studies in HCT-116 human colon carcinoma, OVCAR3 human ovarian carcinoma, NCI-H23 human NSCLC carcinoma, HL-60 human leukemia, and the PDX BL0382 bladder carcinoma. In three of five xenograft lines (HCT-116, HL-60, and BL-0382), F-aza-T-dCyd was more efficacious than aza-T-dCyd. Comparable activity was observed for these two agents against the NCI-H23 and OVCAR3 xenografts. In the HCT-116 study, F-aza-T-dCyd [10 mg/kg intraperitoneal (i.p.), QDx5 for four cycles], produced complete regression of the tumors in all mice with a response that proved durable beyond postimplant day 150 (129 days after the last dose). Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with F-aza-T-dCyd (10 mg/kg i.p., QDx5 for three cycles). In the PDX BL-0382 bladder study, both oral and i.p. dosing of F-aza-T-dCyd (8 mg/kg QDx5 for three cycles) produced regressions that showed tumor regrowth beginning 13 days after dosing. These findings indicate that further development of F-aza-T-dCyd (NSC801845) is warranted. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/20/4/625/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030693PMC
April 2021

Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines.

Clin Epigenetics 2021 03 6;13(1):49. Epub 2021 Mar 6.

Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

Background: Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents.

Results: We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation.

Conclusions: Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01026-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936435PMC
March 2021

The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.

Clin Cancer Res 2021 May 22;27(10):2938-2946. Epub 2021 Feb 22.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Pennsylvania.

Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3-targeting antibody-drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line-derived xenograft (CDX) models.

Experimental Design: B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma ( = 3), rhabdomyosarcoma ( = 4), Wilms tumors ( = 2), osteosarcoma ( = 5), and neuroblastoma ( = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.

Results: The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.

Conclusions: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-4221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127361PMC
May 2021

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures.

Cell Rep 2020 10;33(3):108296

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643325PMC
October 2020

The development of β-selective glycosylation reactions with benzyl substituted 2-deoxy-1,4-dithio-D--pentofuranosides: enabling practical multi-gram syntheses of 4'-Thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) to support clinical development.

Nucleosides Nucleotides Nucleic Acids 2021 16;40(1):68-95. Epub 2020 Oct 16.

Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, Rockville, MD, USA.

The lack of effective methods to perform direct β-selective glycosylation reactions with 2-deoxy-1,4-dithio-D--pentofuranosides has long been a significant stumbling block for the multi-gram synthesis of 4'-thio-2'-deoxy nucleosides. In addition, previously reported methods for the preparation of appropriately substituted 2-deoxy-1,4-dithio-D--pentofuranosides have proven problematic for large scale synthesis. To address these issues, herein we describe the modification and optimization of previously reported methods to allow for the convenient large scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D--pentofuranosides. Furthermore, we describe the development of reaction conditions for β-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D--pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15257770.2020.1832694DOI Listing
June 2021

TGFβ-Directed Therapeutics: 2020.

Pharmacol Ther 2021 01 21;217:107666. Epub 2020 Aug 21.

Developmental Therapeutics Program, DCTD, National Cancer Institute, RM 4-W602, MSC 9735, 9609 Medical Center Drive, Bethesda, MD 20892, USA. Electronic address:

The transforming growth factor-beta (TGFβ) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFβ pathway is co-opted by the tumor to increase fibrotic stroma, to promote epithelial to mesenchymal transition increasing metastasis and producing an immune-suppressed microenvironment which protects the tumor from recognition by the immune system. Compelling preclinical data demonstrate the therapeutic potential of blocking TGFβ function in cancer. However, the TGFβ pathway cannot be described as a driver of malignant disease. Two small molecule kinase inhibitors which block the serine-threonine kinase activity of TGFβRI on TGFβRII, a pan-TGFβ neutralizing antibody, a TGFβ trap, a TGFβ antisense agent, an antibody which stabilizes the latent complex of TGFβ and a fusion protein which neutralizes TGFβ and binds PD-L1 are in clinical development. The challenge is how to most effectively incorporate blocking TGFβ activity alone and in combination with other therapeutics to improve treatment outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2020.107666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770020PMC
January 2021

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets.

Clin Epigenetics 2020 06 25;12(1):93. Epub 2020 Jun 25.

Molecular Pharmacology Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA.

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined.

Results: We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3' exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3'UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5' UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors.

Conclusions: Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00876-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318526PMC
June 2020

Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: A Pediatric Preclinical Testing Consortium report.

Pediatr Blood Cancer 2020 05 23;67(5):e28098. Epub 2020 Jan 23.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: WEE1 is a serine kinase central to the G checkpoint. Inhibition of WEE1 can lead to cell death by permitting cell-cycle progression despite unrepaired DNA damage. AZD1775 is a WEE1 inhibitor that is in clinical development for children and adults with cancer.

Methods: AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts.

Results: AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts.

Conclusions: AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28098DOI Listing
May 2020

A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.

Cancer Cell 2019 12;36(6):660-673.e11

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA. Electronic address:

Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227117PMC
December 2019

Are neuroendocrine negative small cell lung cancer and large cell neuroendocrine carcinoma with WT RB1 two faces of the same entity?

Lung Cancer Manag 2019 Aug 21;8(2):LMT13. Epub 2019 Aug 21.

National Cancer Institute, Division of Cancer Treatment & Diagnosis, Rockville, MD 20850, USA.

Until recently, small cell lung cancer (SCLC) was described as SCLC and SCLC variant, based upon cellular morphology and loss of neuroendocrine markers in the SCLC variant. However, based on recent research advances, driven in part by the increase in comprehensive genomic data, it has become clear that there are multiple SCLC subtypes including an ASCL1 and NEUROD1 low, YAP1 high (SCLC-Y) subtype enriched for WT RB1. Comparing morphological and other features of this SCLC subtype to neuroendocrine negative RB1, KEAP1, STK11 WT LCNEC raises a number of important questions with diagnostic and therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/lmt-2019-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802707PMC
August 2019

Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines.

Cancer Chemother Pharmacol 2019 10 31;84(4):771-780. Epub 2019 Jul 31.

Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

Purpose: Genotoxic agents (GAs) including cisplatin, doxorubicin, gemcitabine, and topotecan are often used in cancer treatment. However, the response to GAs is variable among patients and predictive biomarkers are inadequate to select patients for treatment. Accurate and rapid pharmacodynamics measures of response can, thus, be useful for monitoring therapy and improve clinical outcomes.

Methods: This study focuses on integrating a database of genome-wide response to treatment (The NCI Transcriptional Pharmacodynamics Workbench) with a database of baseline gene expression (GSE32474) for the NCI-60 cell lines to identify mechanisms of response and pharmacodynamic (PD) biomarkers.

Results And Conclusions: Our analysis suggests that GA-induced endoplasmic reticulum (ER) stress may signal for GA-induced cell death. Reducing the uptake of GA, activating DNA repair, and blocking ER-stress induction cooperate to prevent GA-induced cell death in the GA-resistant cells. ATF3, DDIT3, CARS, and PPP1R15A appear as possible candidate PD biomarkers for monitoring the progress of GA treatment. Further validation studies on the proposed intrinsic drug-resistant mechanism and candidate genes are needed using in vivo data from either patient-derived xenograft models or clinical chemotherapy trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-019-03898-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127867PMC
October 2019

Exposure time versus cytotoxicity for anticancer agents.

Cancer Chemother Pharmacol 2019 08 17;84(2):359-371. Epub 2019 May 17.

Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA.

Purpose: Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.

Methods: The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days.

Results: There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen ICs by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC. DNA interactive agents had decreasing ICs with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days' exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached ICs < 10 μM in some cell lines after 11 days.

Conclusions: The results suggest that variations in compound exposure time may reflect either mechanism of action or compound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-019-03863-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127868PMC
August 2019

OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL.

Clin Cancer Res 2019 07 23;25(14):4493-4503. Epub 2019 Apr 23.

Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.

Purpose: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL).

Experimental Design: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX).

Results: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; = 264) than B-lineage ALL (B-ALL; = 1,740; < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. , OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1-77.8 days (treated/control values 2.5-14.0), and disease regression was observed in eight of nine PDXs. A significant reduction ( < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs.

Conclusions: OBI-3424 exerted profound efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635081PMC
July 2019

CD248: A therapeutic target in cancer and fibrotic diseases.

Oncotarget 2019 Jan 29;10(9):993-1009. Epub 2019 Jan 29.

Molecular Pharmacology Branch, Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda 20892, MD, USA.

CD248/endosialin/TEM1 is a type 1 transmembrane glycoprotein found on the plasma membrane of activated mesenchymal cells. CD248 functions during embryo development and is either not expressed or found at very low levels in adult tissues. CD248 is expressed at high levels by malignant sarcoma cells, by the pericyte component of tumor vasculature and by mesenchymal cells in some fibrotic diseases. CD248 is being targeted by several experimental therapeutics including antibodies, antibody drug conjugates, as an antigen for CART cells and in therapeutic vaccines. Although the function of CD248 has yet to be fully elucidated, this protein is a potential broad scope therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398180PMC
January 2019

A Vision from the New Editor-in-Chief.

Mol Cancer Ther 2019 03;18(3):497

National Cancer Institute/National Institutes of Health, Bethesda, Maryland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-19-0094DOI Listing
March 2019

Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models.

Clin Cancer Res 2019 04 18;25(7):2278-2289. Epub 2018 Dec 18.

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.

Purpose: Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy.

Experimental Design: DNA damage and changes in cell signaling following prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line-derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies.

Results: Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment , resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively.

Conclusions: Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445779PMC
April 2019

The NCI Transcriptional Pharmacodynamics Workbench: A Tool to Examine Dynamic Expression Profiling of Therapeutic Response in the NCI-60 Cell Line Panel.

Cancer Res 2018 12 24;78(24):6807-6817. Epub 2018 Oct 24.

Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, Maryland.

: The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs. SIGNIFICANCE: The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-0989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295263PMC
December 2018

Inhibition of Parp1 by BMN673 Effectively Sensitizes Cells to Radiotherapy by Upsetting the Balance of Repair Pathways Processing DNA Double-Strand Breaks.

Mol Cancer Ther 2018 10 3;17(10):2206-2216. Epub 2018 Jul 3.

Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany.

Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 μmol/L) or AG14361 (0.4 μmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 μmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (∼1 hour) and at pharmacologically achievable concentrations BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end-joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-0836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195440PMC
October 2018

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Cancer Med 2017 Aug 1;6(8):1952-1964. Epub 2017 Aug 1.

Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702.

The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3β inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/carboplatin in 20-25% of the SCLC lines. Only 10-15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.1131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548882PMC
August 2017

3D Models of the NCI60 Cell Lines for Screening Oncology Compounds.

SLAS Discov 2017 06 13;22(5):473-483. Epub 2017 Mar 13.

1 Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Lab for Cancer Research, Frederick, MD, USA.

The NCI60 cell line panel screen includes 60 human tumor cell lines derived from nine tumor types that has been used over the past 20+ years to screen small molecules, biologics, and natural products for activity. Cells in monolayer culture in 96-well plates are exposed to compounds for 48 h, and Sulforhodamine B is used to determine cell viability. Data analysis tools such as COMPARE allow classification of compounds based on the pattern of cell line response. However, many compounds highly active in monolayer cell culture fail to show efficacy in vivo. Therefore, we explored 3D culture of the NCI60 panel as a strategy to improve the predictive accuracy of the screen. 3D cultures more closely resemble tumors than monolayer cultures with tighter cell-cell contact and nutrient and oxygen gradients between the periphery and the center. We optimized the NCI60 cell line panel for generating 3D spheroids of a prespecified diameter (300-500 µm) in ultra-low attachment (ULA) plates. Spheroids were classified into four categories based on imaging, and concentration response of select agents in 2D and 3D models is presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2472555217697434DOI Listing
June 2017

PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.

Clin Cancer Res 2017 Jan 20;23(2):523-535. Epub 2016 Jul 20.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy.

Experimental Design: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models.

Results: We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status.

Conclusions: SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation. Clin Cancer Res; 23(2); 523-35. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241177PMC
January 2017

Antibody-drug conjugates for cancer therapy.

Lancet Oncol 2016 06;17(6):e254-e262

Thoracic and GI Oncology Branch, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody-drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody-drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody-drug linker technology. Improved understanding of the mechanistic basis of antibody-drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)30030-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601617PMC
June 2016

Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression.

J Natl Cancer Inst 2016 10 31;108(10). Epub 2016 May 31.

Affiliations of authors: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD (DE, TS, RD, JL, CO, RR, MS, JC, EH, NF, AM); Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (MK, GK, JM, BAT), Biometric Research Program, Division of Cancer Treatment and Diagnosis (EP, DS), and Cancer Therapy Evaluation Program (SM), National Cancer Institute, Rockville, MD.

Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat.

Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations.

Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern.

Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djw122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279282PMC
October 2016

Bromodomain and hedgehog pathway targets in small cell lung cancer.

Cancer Lett 2016 Feb 10;371(2):225-39. Epub 2015 Dec 10.

Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892, USA. Electronic address:

Small cell lung cancer (SCLC) is an extremely aggressive cancer that frequently recurs. Twenty-three human SCLC lines were selected representing varied Myc status. Gene expression of lung cancer, stem-like, hedgehog pathway, and notch pathway genes were determined by RT(2)-PCR array and Exon 1.0 ST array. Etoposide and topotecan concentration response was examined. The IC50's for etoposide and topotecan ranged over nearly 3 logs upon 96 hrs exposure to the drugs. Myc status, TOP2A, TOP2B and TOP1 mRNA expression or topoisomerase 1 and topoisomerase 2 protein did not account for the range in the sensitivity to the drugs. γ-secretase inhibitors, RO429097 and PF-03084014, had little activity in the SCLC lines over ranges covering the clinical Cmax concentrations. MYC amplified lines tended to be more sensitive to the bromodomain inhibitor JQ1. The Smo antagonists, erismodegib and vismodegib and the Gli antagonists, HPI1 and SEN-450 had a trend toward greater sensitivity of the MYC amplified line. Recurrent SCLC is among the most recalcitrant cancers and drug development efforts in this cancer are a high priority.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2015.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738144PMC
February 2016

Comprehensive characterization of the Published Kinase Inhibitor Set.

Nat Biotechnol 2016 Jan 26;34(1):95-103. Epub 2015 Oct 26.

Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nbt.3374DOI Listing
January 2016
-->